PB2154: TP53 GENE MUTATION DIVERSITY IN RUSSIAN PATIENTS WITH B-CELL LYMPHOMAS
Authors: B. Biderman, N. Severina, D. Koroleva, N. Gabeeva, A. Belyaeva, S. Tatarnikova, F. Babaeva, E. Nesterova, Y. Mangasarova, O. Margolin, M. Bagova, A. Magomedova, S. Kravchenko, T. Obukhova, E. Zvonkov, A. Sudarikov
Journal: HemaSphere (2022)

Background: The TP53 gene plays a key role in cell cycle control, DNA repair, initiation of apoptosis, and other critical cellular processes. Mutations of this gene are found in almost all types of malignant neoplasms and the vast majority of cases are associated with poor prognosis. Among hematological malignancies, TP53 gene lesions are most actively studied in CLL, while for other lymphomas fewer data are available so far. Aims: To study the frequency, variation, and allelic load of TP53 mutations in Russian patients with B-cell lymphomas. Methods: The study included 145 DNA samples from patients with B-cell lymphomas admitted to the National Medical Research Center for Hematology (Moscow, Russia) in 2020-2021: 53 patients with DLBCL (29F, 24M, age 25-87 years, median 54 years), 47 patients with MCL (17F, 30M, age 42-73 years, median 59 years) and 45 patients with FL (28F, 17M, age 30-72 years, median 49 years), 16 of them with transformation to DLBCL. Mutations in the TP53 gene (exons 4-10) in most samples were detected using NGS according to Pavlova et al., or Sanger sequencing (7 patients). The clinical significance of the detected variants was assessed using the Seshat online tool based on the UMD TP53 database. Results: TP53 gene mutations were detected in 24 DLBCL patients (45.4%). Out of them were found 21 missense mutations (2 cases in the “hot spots” p.R249M and p.R282W and 2 cases in the same position p.G266), 2 splicing site mutations, and 1 insertion. Also, 16 variants were identified as (likely) pathogenic, 13 of which had a mutation load (VAF) greater than 15%. Of the 8 mutations of unclear significance, 4 had a VAF<10%. Del17p was simultaneously detected in 7 patients with TP53 mutations (out of 11 examined). In the MCL patients mutations were found in 19 cases (40%). 18 of them were missense mutations (4 in the “hot spot” p.R248 and 2 in the same position p.V173) and 1 splicing mutation. 16 variants were identified as (likely) pathogenic and had a VAF>14%. All 3 variants of unclear significance were minor. Chromosome 17 abnormalities were found in 7 MCL patients with TP53 mutations out of 11 studied. In the FL patients, TP53 mutations were detected in 12 cases (26.7%). Out of 8 missense mutations, 4 were in hotspots p.R175H, p.R248Q, p.R249M, p.R273H. Also in this group 2 nonsense mutations, 1 splicing mutation, and 1 deletion were observed. Of the 9 variants recognized as (likely) pathogenic, only 1 was minor, as were 2 variants of unclear significance. Only 1 patient with TP53 mutation out of 6 examined had del17p. All results are presented in Table 1. Image:Summary/Conclusion: The frequency of mutations in the TP53 gene in patients with B-cell lymphomas in our sample is significantly higher than according to the literature data. One can explain this bias by patient selection. A significant portion of DLBCL and FL patients admitted to our center in the state of progression or relapse. Most MCL cases were primary, however, MCL patients with advanced stages of the disease are more often admitted to the National Medical Research Center for Hematology. At the same time, the occurrence of “hot spots” mutations in MCL and FL is also higher than expected. Further studies concerning the type of mutations, their allelic load, and their combination with 17th chromosome lesions in association with disease course are on the way.